Regulation of AMPA Receptors by Phosphorylation

The AMPA receptors for glutamate are oligomeric structures that mediate fast excitatory responses in the central nervous system. Phosphorylation of AMPA receptors is an important mechanism for short-term modulation of their function, and is thought to play an important role in synaptic plasticity in different brain regions. Recent studies have shown that phosphorylation of AMPA receptors by cAMP-dependent protein kinase (PKA) and Ca2+- and calmodulin-dependent protein kinase II (CaMKII) potentiates their activity, but phosphorylation of the receptor subunits may also affect their interaction with intracellular proteins, and their expression at the plasma membrane. Phosphorylation of AMPA receptor subunits has also been investigated in relation to processes of synaptic plasticity. This review focuses on recent advances in understanding the molecular mechanisms of regulation of AMPA receptors, and their implications in synaptic plasticity.     

Leptin leads hypothalamic feeding circuits in a new direction

A decade ago, leptin (from the greek lepto meaning 'thin') was identified as the product of the ob gene.1 This adipocyte-derived hormone was found to suppress feeding and stimulate thermogenesis, and was thus proposed as a mediator in a negative feedback loop that controls body adiposity. This discovery led to a rapid revolution in the understanding of neurobiological mechanisms regulating obesity. However, while leptin's first life was as an adipostat, it is now known to have a wide range of additional neuroendocrine, metabolic and behavioural functions in the CNS and periphery. Remarkably, the pleiotropic nature of the hormone continues to be extended with the recent publication of two papers that expand on leptin's neurobiological actions in the CNS.2,3 They indicate novel regulatory roles for the hormone in both synaptic plasticity and axon guidance. Crucially, in light of the rising incidence of obesity in modern society, both of the studies reveal leptin-mediated links between nutrition and neurodevelopment, findings that have further implications for leptin's role in the regulation of energy homeostasis.     

Adiposity signals and food reward: expanding the CNS roles of insulin and leptin

The hormones insulin and leptin have been proposed to act in the central nervous system (CNS) as adiposity signals as part of a theoretical negative feedback loop that senses the caloric stores of an animal and orchestrates adjustments in energy balance and food intake. Much research has provided support for both the existence of such a feedback loop and the specific roles that insulin and leptin may play. Most studies have focused on hypothalamic sites, which historically are implicated in the regulation of energy balance, and on the brain stem, which is a target for neural and humoral signals relating to ingestive acts. More recent lines of research, including studies from our lab, suggest that in addition to these CNS sites, brain reward circuitry may be a target for insulin and leptin action. These studies are reviewed together here with the goals of providing a historical overview of the findings that have substantiated the originally hypothesized negative feedback model and of opening up new lines of investigation that will build on these findings and allow further refinement of the model of adiposity signal/CNS feedback loop. The understanding of how motivational circuitry and its endocrine or neuroendocrine modulation contributes to normal energy balance regulation should expand possibilities for future therapeutic approaches to obesity and may lead to important insights into mental illnesses such as substance abuse or eating disorders.     

Synaptic Neurotransmitter-Gated Receptors

Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.To understand how neurons communicate with each other requires a fundamental understanding of neurotransmitter receptor structure and function. Neurotransmitter-gated ion channels, also known as ionotropic receptors, are responsible for fast synaptic transmission. They decode chemical signals into electrical responses, thereby transmitting information from one neuron to another. Their suitability for this important task relies on their ability to respond very rapidly to the transient release of neurotransmitter to affect cell excitability.In the central nervous system (CNS), fast synaptic transmission results in two main effects: neuronal excitation and inhibition. For excitation, the principal neurotransmitter involved is glutamate, which interacts with ionotropic (integral ion channel) and metabotropic (second-messenger signaling) receptors. The ionotropic glutamate receptors are permeable to cations, which directly cause excitation. Acetylcholine and serotonin can also activate specific cation-selective ionotropic receptors to affect neuronal excitation. For controlling cell excitability, inhibition is important, and this is mediated by the neurotransmitters GABA and glycine, causing an increased flux of anions. GABA predominates as the major inhibitory transmitter throughout the CNS, whereas glycine is of greater importance in the spinal cord and brainstem. They both activate specific receptors—for GABA, there are ionotropic and metabotropic receptors, whereas for glycine, only ionotropic receptors are known to date.Together with acetylcholine- and serotonin-gated channels, GABA and glycine ionotropic receptors form the superfamily of Cys-loop receptors, which differs in many aspects from the superfamily of ionotropic glutamate receptors. Over the last two decades, our knowledge of the structure and function of ionotropic receptors has grown rapidly. In this article, we summarize our current understanding of the molecular operation of these receptors and how we can now begin to interpret the role of receptor structure in agonist binding, channel activation, and allosteric modulation of Cys-loop and glutamate receptor families. Further details on the regulation and trafficking of neurotransmitter receptors in synaptic structure and plasticity can be found in accompanying articles.     

Molecular Bases of Caloric Restriction Regulation of Neuronal Synaptic Plasticity

Aging is associated with the decline of cognitive properties. This situation is magnified when neurodegenerative processes associated with aging appear in human patients. Neuronal synaptic plasticity events underlie cognitive properties in the central nervous system. Caloric restriction (CR; either a decrease in food intake or an intermittent fasting diet) can extend life span and increase disease resistance. Recent studies have shown that CR can have profound effects on brain function and vulnerability to injury and disease. Moreover, CR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which modulate pain sensation, enhance cognitive function, and may increase the ability of the brain to resist aging. The beneficial effects of CR appear to be the result of a cellular stress response stimulating the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors, neurotransmitter receptors, protein chaperones, and mitochondrial biosynthesis regulators. In this review, we will present and discuss the effect of CR in synaptic processes underlying analgesia and cognitive improvement in healthy, sick, and aging animals. We will also discuss the possible role of mitochondrial biogenesis induced by CR in regulation of neuronal synaptic plasticity.     

Regulation of AMPA Receptor Activity, Synaptic Targeting and Recycling: Role in Synaptic Plasticity

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors for the neurotransmitter glutamate are oligomeric structures responsible for most fast excitatory responses in the central nervous system. The activity of AMPA receptors can be directly regulated by protein phosphorylation, which may also affect the interaction with intracellular proteins and, consequently, their recycling and localization to defined postsynaptic sites. This review focuses on recent advances in understanding the dynamic regulation of AMPA receptors, on a short- and long-term basis, and its implications in synaptic plasticity.     

GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition

GABA (gamma-aminobutyric acid) type A receptors (GABA(A)Rs) mediate most fast synaptic inhibition in the mammalian brain, controlling activity at both the network and the cellular levels. The diverse functions of GABA in the CNS are matched not just by the heterogeneity of GABA(A)Rs, but also by the complex trafficking mechanisms and protein-protein interactions that generate and maintain an appropriate receptor cell-surface localization. In this Review, we discuss recent progress in our understanding of the dynamic regulation of GABA(A)R composition, trafficking to and from the neuronal surface, and lateral movement of receptors between synaptic and extrasynaptic locations. Finally, we highlight a number of neurological disorders, including epilepsy and schizophrenia, in which alterations in GABA(A)R trafficking occur.     

Role of glia-derived cholesterol in synaptogenesis: new revelations in the synapse-glia affair.

Brain development and function relies on the exchange of signals between neurons and glial cells. Here we review a series of recent studies on cultures of purified retinal ganglion cells (RGCs) that point to a new role of glial cells in the formation and plasticity of synaptic connections. The results suggest that neurons must import glia-derived cholesterol via lipoproteins to form numerous and efficient synaptic connections. This finding may explain why throughout the central nervous system (CNS) the main phase of synaptogenesis starts synchronously after glia differentiation and why astrocytes produce apolipoprotein E (apoE) and cholesterol-containing lipoproteins. Experimental tests of these hypotheses may further our understanding of the cholesterol metabolism in the brain and may help to explain neurologic symptoms resulting from defective cholesterol and lipoprotein metabolism.     

Steroid-induced hippocampal synaptic plasticity: sex differences and similarities

Early in development, steroid hormones structurally organize various regions of the CNS. However, steroid hormones continue to affect the structure and function of the CNS throughout the life of the individual. In this review, we discuss sex differences and similarities in steroid-induced synaptic plasticity in the adult brain. Particular emphasis is placed on steroid-induced plasticity in the hippocampus, a brain region important in learning and memory. This topic is relevant to the growing evidence for the actions of sex hormones outside of the reproductive neuroendocrine axis. It also tells an important and emerging story about non-genomic and genomic actions of steroids at the cellular and molecular levels. Specifically, the effects of estrogen and progesterone as well as the androgens and glucocorticoids are discussed. The influence of steroids on hippocampal structure and function can differ vastly between the sexes. However, there are certain similarities that might aid in our understanding of how steroids affect CNS plasticity in general. Although future studies will undoubtedly lead us to a greater understanding of these phenomena, the data reviewed indicate that when studying synaptic plasticity, the sex and hormonal milieu of the individual might significantly influence the outcome and interpretation of the research.     

Neuron-astrocyte signaling in the development and plasticity of neural circuits

Emerging evidence indicates that signaling between perisynaptic astrocytes and neurons at the tripartite synapse plays an important role during the critical period when neural circuits are formed and refined. Cross-talk between astrocytes and neurons during development mediates synaptogenesis, synapse elimination and structural plasticity through a variety of secreted and contact-dependent signals. Recent live imaging studies reveal a dynamic and cooperative interplay between astrocytes and neurons at synapses that is guided by a variety of molecular cues. A unifying theme from these recent findings is that astrocytes can promote the development and plasticity of synaptic circuits. Insight into the molecular mechanisms by which astrocytes regulate the wiring of the brain during development could lead to new therapeutic strategies to promote repair and rewiring of neural circuits in the mature brain following CNS injury and neurodegenerative disease.     

Phosphorylation of ligand-gated ion channels: a possible mode of synaptic plasticity.

Most neurotransmitter receptors examined to date have been shown either to be regulated by protein phosphorylation or to contain consensus sequences for phosphorylation by protein kinases. Neurotransmitter receptors that mediate rapid synaptic transmission in the nervous system are the ligand-gated ion channels and include the nicotinic acetylcholine receptors of muscle and nerve and the excitatory and inhibitory amino acid receptors: the glutamate, GABAA, and glycine receptors. These receptors are multimeric proteins composed of homologous subunits which each span the membrane several times and contain a large intracellular loop that is a mosaic of consensus sites for protein phosphorylation. Recent evidence has suggested that extracellular signals released from the presynaptic neuron, such as neurotransmitters and neuropeptides as well as an extracellular matrix protein, regulate the phosphorylation of ligand-gated ion channels. The functional effects of phosphorylation are varied and include the regulation of receptor desensitization rate, subunit assembly, and receptor aggregation at the synapse. These results suggest that phosphorylation of neurotransmitter receptors represents a major mechanism in the regulation of their function and may play an important role in synaptic plasticity.     

Leptin and its role in hippocampal synaptic plasticity

It is well documented that the hormone leptin plays a pivotal role in regulating food intake and body weight via its hypothalamic actions. However, leptin receptors are expressed throughout the brain with high levels found in the hippocampus. Evidence is accumulating that leptin has widespread actions on CNS function and in particular learning and memory. Recent studies have demonstrated that leptin-deficient or-insensitive rodents have impairments in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze. Moreover, direct administration of leptin into the brain facilitates hippocampal long-term potentiation (LTP), and improves memory performance in mice. There is also evidence that, at the cellular level, leptin has the capacity to convert hippocampal short-term potentiation (STP) into LTP, via enhancing NMDA receptor function. Recent data indicates that leptin can also induce a novel form of NMDA receptor-dependent hippocampal long-term depression. Here, we review the evidence implicating a key role for the hormone leptin in modulating hippocampal synaptic plasticity and discuss the role of lipid signaling cascades in this process.     

Mechanisms of GABAA receptor assembly and trafficking: implications for the modulation of inhibitory neurotransmission

Fast synaptic inhibition in the brain is largely mediated by ionotropic GABA receptors, which can be subdivided into GABAA and GABAC receptors based on pharmacological and molecular criteria. GABAA receptors are important therapeutic targets for a range of sedative, anxiolytic, and hypnotic agents and are implicated in several diseases including epilepsy, anxiety, depression, and substance abuse. In addition, modulating the efficacy of GABAergic neurotransmission may play a key role in neuronal plasticity. Recent studies have begun to reveal that the accumulation of ionotropic GABAA receptors at synapses is a highly regulated process that is facilitated by receptor-associated proteins and other cell-signaling molecules. This review focuses on recent experimental evidence detailing the mechanisms that control the assembly and transport of functional ionotropic GABAA receptors to cell surface sites, in addition to their stability at synaptic sites. These regulatory processes will be discussed within the context of the dynamic modulation of synaptic inhibition in the central nervous system (CNS).     

Glia as mediators of steroid hormone action on the nervous system: An overview.

This special issue on steroids and glia represents the intersection of two emerging themes in the neurosciences: (a) Glia actively modulate and participate in brain function throughout life, and (b) glia are sensitive to steroid hormones. This overview begins by reviewing some of the basic principles of steroid hormone action on the brain and introducing the various glia that inhabit the peripheral and central nervous system. A prominent theme among the articles that follow is that glia may be direct targets for steroid hormones since they possess steroid receptors and the promoter region of glial-specific genes such as glutamine synthetase contain hormone-responsive elements. The articles in this special issue discuss evidence that glia may mediate steroid action on the nervous system in the context of (a) steroid metabolism, which may control the hormonal microenvironment of neurons both in the normal and injured brain; (b) brain development including sexual differentiation; (c) synaptic plasticity which may underlie the cyclic release of luteinizing hormone releasing hormone in the female rodent brain; (d) neural repair and aging; and (e) brain immune function. Another theme among these articles is that glia influence neurons via specific secreted and cell-surface molecules, and that steroids affect this mode of communication by altering the level of glial production of these signaling molecules and/or the sensitivity of neurons to such signals.     

Localization of mineralocorticoid receptors at mammalian synapses

In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.     

PSA-NCAM: Synaptic functions mediated by its interactions with proteoglycans and glutamate receptors

Dynamic regulation of glycosylation of the neural cell adhesion molecule (NCAM) by an unusual large negatively charged polysialic acid (PSA) is the major prerequisite for correct formation of brain circuitries during development and for normal synaptic plasticity, learning and memory in the adult. Traditionally, PSA is viewed as a de-adhesive highly hydrated molecule, which interferes with cell adhesion and promotes cellular/synaptic dynamics by steric hindrance. Analysis of synaptic functions of PSA-NCAM highlighted additional features of this molecule. First, PSA promotes interaction of NCAM with heparan sulfate proteoglycans and thus stimulates synaptogenesis. Second, PSA-NCAM modulates glutamate receptors: it restrains activity of extrasynaptic GluN2B-containing NMDA receptors and facilitates activity of a subset of AMPA receptors. Perturbation in polysialylation and/or NCAM expression in mouse models recapitulates many symptoms of human brain disorders such as schizophrenia, depression, anxiety and Alzheimer's disease.     

Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis

Type 2 diabetes mellitus (DM) appears to be a significant risk factor for Alzheimer disease (AD). Insulin and insulin-like growth factor-1 (IGF-1) also have intense effects in the central nervous system (CNS), regulating key processes such as neuronal survival and longevity, as well as learning and memory. Hyperglycaemia induces increased peripheral utilization of insulin, resulting in reduced insulin transport into the brain. Whereas the density of brain insulin receptor decreases during age, IGF-1 receptor increases, suggesting that specific insulin-mediated signals is involved in aging and possibly in cognitive decline. Molecular mechanisms that protect CNS neurons against β-amyloid-derived-diffusible ligands (ADDL), responsible for synaptic deterioration underlying AD memory failure, have been identified. The protection mechanism does not involve simple competition between ADDLs and insulin, but rather it is signalling dependent down-regulation of ADDL-binding sites. Defective insulin signalling make neurons energy deficient and vulnerable to oxidizing or other metabolic insults and impairs synaptic plasticity. In fact, destruction of mitochondria, by oxidation of a dynamic-like transporter protein, may cause synapse loss in AD. Moreover, interaction between Aβ and τ proteins could be cause of neuronal loss. Hyperinsulinaemia as well as complete lack of insulin result in increased τ phosphorylation, leading to an imbalance of insulin-regulated τ kinases and phosphatates. However, amyloid peptides accumulation is currently seen as a key step in the pathogenesis of AD. Inflammation interacts with processing and deposit of β-amyloid. Chronic hyperinsulinemia may exacerbate inflammatory responses and increase markers of oxidative stress. In addition, insulin appears to act as 'neuromodulator', influencing release and reuptake of neurotransmitters, and improving learning and memory. Thus, experimental and clinical evidence show that insulin action influences cerebral functions. In this paper, we reviewed several mechanisms by which insulin may affect pathophysiology in AD.     

Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo

Experience-dependent regulation of synaptic strength has been suggested as a physiological mechanism by which memory storage occurs in the brain. Although modifications in postsynaptic glutamate receptor levels have long been hypothesized to be a molecular basis for long-lasting regulation of synaptic strength, direct evidence obtained in the intact brain has been lacking. Here we show that in the adult brain in vivo, synaptic glutamate receptor trafficking is bidirectionally, and reversibly, modified by NMDA receptor-dependent synaptic plasticity and that changes in glutamate receptor protein levels accurately predict changes in synaptic strength. These findings support the idea that memories can be encoded by the precise experience-dependent assignment of glutamate receptors to synapses in the brain.     

Integration of physiological mechanisms that influence fertility in dairy cows

Fertility in dairy cows has been declining for the past three decades. Genetic selection for increased milk production has been associated with changes in key metabolic hormones (growth hormone, insulin, IGF and leptin) that regulate metabolism by homoeostasis and homeorhesis. These metabolic hormones, particularly insulin, provide signals to the reproductive system so that regulation of ovarian function is coordinated with changes in metabolic status. Studies have shown, for example, that increasing circulating insulin concentrations during the early post partum period can advance the resumption of oestrous cycles by enhancing follicular growth. However, high concentrations of insulin can be detrimental to the developmental competence of oocytes, which is also influenced by the supply of fatty acids at the systemic level and at the ovarian level. Insulin status is also associated with the incidence and characteristics of abnormal ovarian cycles. These changes can occur without significant variation in circulating gonadotrophin concentrations. This suggests that additional factors, such as peripheral metabolites, metabolic hormones and locally produced growth factors, may have a modulating role. Recent evidence has demonstrated that ovarian responses to metabolic signals and nutrient profile vary according to the stage of the reproductive cycle. Improved understanding of this multifactorial process enables nutrition to be matched to genotype and milk production, with a positive impact on pregnancy rate.